The specific aims of this project are to determine the effects of nicotine administration and deprivation on changes in emotional processing among smokers carrying the DRD2 A1 and A2 alleles. Data from our laboratory suggest that smokers carrying the A1 allele vs. those with only the A2, are both less likely to quit smoking and experience less consistent negative affect reduction when exposed to a treatment involving antidepressant (venlafaxine) therapy. This suggests that the A1 allele may modulate the effects of a psychotropic agent on mood while quitting, and by implication may influence the direction and magnitude of affective changes associated with nicotine exposure. Understanding the relationship between genetic factors, nicotine and mood, may help us identify the most salient properties of smoking for particular groups of individuals (e.g., positive mood enhancement, negative affect reduction), and select treatments which seek to alter this relationship in a beneficial way (e.g., reinforcement blockade and mood modulating drugs). However, procedures for studying the effects of nicotine on mood have largely been limited to self-report. While important, these methods rely heavily on cognitive appraisal and cannot assess the near instantaneous neurophysiological activity thought to precede a change in affect. In this study, we will use the startle response as an index of reactivity to affective stimuli. The startle reflex (eye blink) is an orienting response that follows an unexpected auditory stimulus (startle probe), and may reflect immediate changes in underlying cortical and subcortical processes associated with drive or motivational states (e.g., appetitive/defensive; approach/avoidance). Negative emotional cues delivered prior to the probe increase the blink response magnitude (eye muscle EMG), while positive cues reduce or inhibit the response. This startle-affect relationship provides an ideal paradigm for studying the effects of acute nicotine administration and withdrawal on mood and allows comparisons between smokers with more or less vulnerability to become nicotine dependent (e.g. A1 allele types) and/or those who may have more difficulty quitting. Using a 2x2x2x3 factorial design, we will determine if the magnitude and latency of the startle response is influenced by genotype (A1/A1 and A1/A2 or A2/A2), level of nicotine withdrawal (overnight deprived or non- deprived), acute administration of nicotine (nicotine or placebo), and the affective valance (positive, negative, neutral) of emotional stimuli. Two groups of smokers (60 with and without the A1 allele), stratified by race, gender and depression history, will be exposed to four counterbalanced laboratory assessments, completely crossing the 2 levels of pre-session nicotine withdrawal (deprivation/non-deprived) with 2 levels of within session drug administration (nasal nicotine administration or placebo). Within each session, participants will receive 2 blocks of startle probe trials, associated with exposure to emotional cues (standardized slides) selected for 3 levels of affective valence (positive, negative or neutral). The first will be preceded by placebo and the second by either nicotine nasal spray or placebo, depending on the session. Differences in startle intensity and latency between the first trial block (placebo) and the second (placebo or nicotine) will be compared across the four sessions. We hypothesize an enhanced startle response (increased magnitude/decreased latency) for negative vs positive cues, presence of the A1 allele (A1/A1 +A2/A1 greater than A2/A2); deprived vs. nondeprived; and nicotine vs. placebo conditions. A1 smokers are also expected to show significantly enhanced responding to negative stimuli and greater attenuation of responding by nicotine. In exploratory analyses, we will also assess the modulating effects of other candidate genes (DRD4 and SLC6A3) on these relationships. Confirmation of these hypotheses will provide evidence for nicotine's action as a mood modulator and the importance of genetic factors related to dopamine neurotransmission in determining the direction and magnitude of these effects.